School of Medicine, Wuhan University of Science and Technology, Wuhan, China; Department of Nephrology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
Department of Nephrology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113424. doi: 10.1016/j.intimp.2024.113424. Epub 2024 Oct 21.
The role of B-cell lymphoma 2 (BCL2)-associated X (BAX) macropores in the leakage of mitochondrial DNA (mtDNA) and their impact on acute kidney injury (AKI) has recently been brought to the focus of researchers. This study aimed to explore the relationship between mtDNA leakage and BAX macropores during wasp sting-induced AKI. BAX mitochondrial translocation and macropores opening increased in both in vivo and in vitro models of wasp sting-induced AKI. In a mouse model, BAX inhibition dramatically attenuated mitochondrial impairment, cytoplasmic release of mtDNA, and suppressed activation of the mtDNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. This attenuation improved kidney function, reduced inflammatory response, and decreased apoptosis in mouse models. Furthermore, in cultured human proximal tubular epithelial cells (HK-2) treated with myoglobin and subjected to BAX knockdown, quantitative real-time polymerase chain reaction (PCR) directly demonstrated decreased mtDNA release into the cytoplasm. Consistent with in vivo results, downregulation of BAX expression in vitro ameliorated mitochondrial damage and attenuated subsequent inflammation and apoptosis caused by the activation of the mtDNA-cGAS-STING signaling pathway. Our findings revealed that mtDNA is released into the cytoplasm through BAX macropores in wasp sting-induced AKI, which provided an important novel perspective for understanding wasp sting-induced AKI and is conducive for identifying novel therapeutic targets and strategies.
B 细胞淋巴瘤 2（BCL2）相关 X（BAX）大孔在线粒体 DNA（mtDNA）漏出及其对急性肾损伤（AKI）的影响方面的作用最近引起了研究人员的关注。本研究旨在探讨黄蜂蜇伤诱导 AKI 过程中 mtDNA 漏出与 BAX 大孔之间的关系。黄蜂蜇伤诱导 AKI 的体内和体外模型中，BAX 线粒体易位和大孔开放增加。在小鼠模型中，BAX 抑制显著减弱了线粒体损伤、细胞质中 mtDNA 的释放，并抑制了 mtDNA-cyclic GMP-AMP 合酶（cGAS）-干扰素基因刺激物（STING）信号通路的激活。这种减弱改善了肾功能，减轻了炎症反应，并减少了小鼠模型中的细胞凋亡。此外，在用肌红蛋白处理并进行 BAX 敲低的培养人近端肾小管上皮细胞（HK-2）中，实时定量聚合酶链反应（PCR）直接证明细胞质中 mtDNA 释放减少。与体内结果一致，体外下调 BAX 表达改善了线粒体损伤，并减弱了随后由 mtDNA-cGAS-STING 信号通路激活引起的炎症和细胞凋亡。我们的研究结果表明，在黄蜂蜇伤诱导的 AKI 中，mtDNA 通过 BAX 大孔释放到细胞质中，这为理解黄蜂蜇伤诱导的 AKI 提供了一个重要的新视角，并有助于确定新的治疗靶点和策略。
